Project Summary (Abstract) This proposal aims to investigate the impact of inflammation on clonal dominance in myeloid leukemogenesis. For my doctoral research, I am investigating the pathogenesis of a class of chronic hematologic malignancies known as the myeloproliferative neoplasms (MPNs). The MPNs are clonal malignancies that are characterized by the overproduction of mature myeloid cell types, and by somatic activating mutations in JAK2 (Specifically the JAK2V617F mutation). The long-term goal of my doctoral training, outlined in Specific Aims 1 and 2, is to elucidate the impact of JAK2V617F-mutant cells on the wild-type hematopoietic milieu, and how this interaction contributes to the pathogenesis of myeloproliferative neoplasms. Little is known about how specific myeloid cell lineages contribute to the pathogenesis and phenotypic presentation of this diverse class of diseases. In order to investigate the consequences of Jak2 gain-of-function on megakaryocyte/platelet development and proliferation, I generated a novel mouse model of megakaryocyte-specific Jak2 activation. I have extensively characterized the hematopoietic phenotype of this model, and my preliminary data reveals that Jak2-mutant megakaryocytes and platelets stimulate aberrant erythroid cell proliferation, likely via activation of a chronic inflammatory response (discussed in Specific Aim 1). The remaining 2 years of my doctoral training will be dedicated to probing 2 main questions, as outlined in Specific Aim 2: (1) What is the effect of Jak2-mutant megakaryocytes/platelets on myeloid cell activation and inflammatory responses in the periphery? (2) What is the effect of JAK2V617F on Stat5 transcriptional activity in primary megakaryocytes? To date, no study has directly addressed these questions and there are no published data investigating the effects of mutant MPN cells on wild-type hematopoietic cells in vivo. For my postdoctoral fellowship, discussed in Specific Aim 3, I will expand upon my doctoral training to investigate the role of chronic inflammation and the tumor microenvironment in the pathogenesis of Acute Myeloid Leukemia (AML). Collectively, the experiments and research proposed in this fellowship application will generate new mouse models of myeloid malignancies, and mechanistic insight into the cell non- autonomous events of myeloid cell transformation and leukemogenesis. There are no curative treatments for either MPN or AML, besides stem cell transplants. My planned research will offer new insights into the molecular evolution of these diseases, which will ultimately lead to new avenues for therapeutic intervention for these diseases.